Thionocarbonate nucleosides



3,322,747 Patented May 30, 1967 3,322,747 'lHlflNDCARBONATE NUCLEOSIDESTsung-Ying Shen, Westtield, and William V. Ruyle, Scotch Plains, NJ,assignors to Merck & (30., Inc,

Rahway, N..l., a corporation of New Jersey No Drawing. Filed Apr,1,1965, Ser. No. 444,803 20 Claims. (6i. 260-2115) This inventionrelates generally to nucleosides and more particularly to novelsubstituted nucleosides useful in the preparation of a wide variety ofother nueleosides. Specifically, it relates to novel ri'bonucleosideshaving a thionocarbonate grouping at the 2',3-position of the ribosemoiety, to novel methods for preparing them, and to novel methods forconverting them into other nueleosides.

It is an object of the present invention to provide novelthionocarbonate nucleosides which may be converted into a variety ofnueleosides.

It is another object of the invention to provide novel processes forobtaining said novel thionocarbonate's.

It is a further object of the invention to provide an overall processfor the convenient conversion of a riboside to an arabinoside.

These and other objects will appear from the detailed description Whichfollows.

The novel compounds of the present invention have the followingstructural formula 4 HNB 5 wherein R is the acyl residue of an organiccarboxylic acid, alkyl, or aralkyl, and R is hydrogen, halogen, alkyl,amine, alkylamine such as methylamine, dimethylamine, pro-pylamine, andthe like, or trifluoromethyl. In general, compounds I may be termed1-(5-O-R-fi-D- ribofuranosyl)- or 6-(R-uracil-2',3-O-thionocarbonates.Typical of the foregoing R groups are alkyl such as methyl, ethyl,butyl, and pentyl, aralkyl such as trityl, benzyl, p-nitrobenzyl, andp-chlorobenzyl, and acyl groups such as those derived from organiccarboxylic acids, which groups are exemplified by acetyl, propionyl,buty-ryl, benzoyl, substituted benzoyl such as p-nitrobenzoyl andp-chlorobenzoyl, and the like. Illustrative of compounds Iare 1-(5-O-trity1-,8-D ribofurano syl) -uracil-2,3'-O-thionocarbonate,

1( 5'-O-trityl-B-D-ribofuranosyl -5 -ch-lor-ouracil-2',3 '-O-thionocarbonate,

l- 5 '-O-trityl-,B-D-ribofuranosyl) -5-methylaminouracil- 2,3'-O-thionocar-bonate,

1-( 5 -O-trityl-;i-D-ri-b ofuranosyl -5-methyluracil-2',3

O-thionocarbonate,

1- (5 '-O-trity1/3-D-ribofuranosyl) -5 -trifluor-omethyluracil- 2,3'-O-thionocarbonate,

1-( 5 -O-benzy1- 8-D-ribofuranosy1) -uracil-2,3'-O-thionocarbonate,

1- 5'-O-benzyl-B-D-ribofuranosyl -5-bromouracil-2',3

O-thionocarbonate,

1- 5 '-O-benzyl- 8-D-ribofuranosyl) -5-aminouracil-2',3

O-thionocarbonate, I

1- (5 -O-acetyl-,8-D-ribofuranosyl) -uracil-2,3 -O-thionocarbonate,

1- 5 -O-acetyl-5-D-'rib ofuranosyl) -5-trifluoromethyluracil-2',3'-O-thionocanbonate,

1- (5-O-benzoyl-, 3-D-ribofuranosyl) -uracil-2,3 '-O- thionocarbonate,

1- (5-O-benzoyl-fl-D-ribofuranosyl) -5-brom0uracil-2',3

O-thionocarbonate, and

1- 5 '-O-=benzoyl-fl-D-ribofuranosyl) -5-ethy1uracil- 2,3'-O-thionocarbonate.

Preferred among the foregoing are the compounds Wherein R is t-rityl andmost preferred is 1-(5-O-trityl-fi-D-rihofuranosyl)-uracil-2',3-O-thionocarbonate.

In general, the compounds of the present invention are prepared bytreating the appropriate ribonucleoside, suitably protected at the SO-position preferably, as mentioned previously, with the trityl group,with a thionocarbonate generating system such as is obtained fromthiophosgene in the presence of a tertiary amine such as pyridine,triethylamine, N-ethylpiperidine, and the like. Such ri'bonucleosidesare shown as compounds II below. Alternatively, and preferably, thethionocarbonate generating material is bis-(imidazol-l-yl)-thione. Thereaction should be carried out at less than about C. and preferablybetween 0 and 30 C. In this regard, it has been discovered that attemperatures higher than 110 C. further reactions occur resulting in theformation of the O ,2',3-a'nhydro nucleoside. The following diagramillustrates the formation of compounds I.

(III) wherein R and R are as previously defined. This may be done in thesame reaction system employed for the formation of compounds I merely byincreasing the temperature of the system to point of reflux or bydirectly heating compounds II. As the base there may be employed slightexcesses of the bis-imidazolyl reagent, although any other base may 'beemployed. In this regard, the reaction proceeds readily in the presenceof even very weak bases. It will be appreciated by those skilled in theart that the irnidazolyl reagent is itself a very weak base. CompoundsIII are generally termed O-2-anhydro-1-(5'-O-R-B-D-ribofuranosyl)-uracils. They may be hydrolyzed,preferably with acid, to cleave the 2,2'-oxygen-ether linkage and formthe hydroxyl group at the 2-position in the arabinose form. They maythen be converted, in accordance with known techniques, to compoundssuch as cytosine arabinoside which is a known antiviral, antibacterialcompound.

Compounds I may also be converted to 2',3'-dideoxyriboside-2',3'-olefinsof the formula where R and R are as previously defined. This may be doneby reducing compounds I preferably using Raney nickel as a catalyst inthe presence of suitable solvents such as ketones as, for example,acetone, methylethylketone, and the like; esters such as ethylacetate;alkanols such as methanol and ethanol; and the like. The temperature ofconversion is suitably the reflux temperature of the particular systememployed. The conversion may be effected without the prior isolation ofcompounds I and thus represents a short, convenient method for thepreparation of 2,3'-dideoxyriboside directly from the riboside. There isalso obtained in the reaction mixture varying amounts of compounds III,depending on the amount of alkalinity introduced into the system. Thus,the presence of residual alkalinity in the Raney nickel will cause thecyclonucleoside to form. Minimizing this alkalinity will promote highyields of compounds IV. The two components, when formed, may beseparated by fractional crystallization, chromatography, and the like.Compounds IV wherein R is R" and R" is chloro, trifiuoromethyl, amino,alkyl having two or more carbon atoms, alkylamino, or dialkylamino suchas methylamino, ethylamino, butylamino, dimethylamino, dibutylamino, andthe like, are novel and are antimicrobial agents, are useful in thepreparation of potent antimetabolites and are, therefore, useful in thestudy of metabolic and biological systems. Such compounds arerepresented by 1- 'O-trityl-l3-D-ribofuranosyl -2',3-dideoxy-2,

3'-didehydro-5-chlorouracil,1-(5-O-trityl-fl-D-ribofuranosyl)-2',3-dideoxy-2',

3'-didehydro-5-aminouracil,1-(5'-Otrityl-,8-D-ribofuranosyl)-2,3'-dideoxy-2',3-

didehydro-S-trifiuoromethyluracil, 1- (5-O-trityl-[i-D-ribofuranosyl-2',3 -dideoxy-2,3

didehydro-S-methylaminouracil, 1-(5'-O-trityl-8-D-ribofuranosyl)-2',3-dideoxy- 2',3-didehydro-5-dimethylaminouracil,1-(5'-O-benzyl-,B-D-ribofuranosyl)-2',3'-dideoxy-2,3'-didehydro-5-chlorouracil,1-(5'-O-benzyl-B-D-ri*bofuranosyl)-2',3'-dideoxy-2,3-didehydro-5-aminouracil, and1-(5'-O-acety1-B-D-ribofuranosyl)-2.,3'-

dideoxy-2,3-didehydro-5-methylaminouraci1.

Alternatively, compounds I may be treated with an alkylphosphite to formthe novel N -alkylated compounds of the formula H H (V) where R" is thealkyl group corresponding to the alkylphosphite used and R and R are aspreviously defined. The preferred phosphite is trimethylphosphite,although other alkyl phosphites such as the triethyl and tributylcompounds may be employed as desired. Representative of compounds Vwhich are useful, as are compounds IV, are the following:

i illustration only and are not intended to limit the scope of theinvention.

EXAMPLE 1 1-(5-O-trityl-fl-D-ribofuranosyl)-uracil-2,3'-0-thionocarbonate A solution of1-(5'-O-trityl-B-D-ribofuranosyl)-uracil (0.486 g. l mmole) andbis-(imidazol-l-yl)-thione (0.2 g., 1.1 mmoles) in 5 ml. oftetrahydrofuran is kept at 25 C. for five days. The crude product isprecipitated with petroleum benzin, then taken up in chloroform andwashed with water. After removal of solvent, the product is redissolvedin ether, and a small amount of insoluble material removed byfiltration. Hexane is added to the filtrate to precipitate 350 mg. of1-(5'-O-trityl-;9-D- ribofuranosyl)-uracil-2',3-O-thionocarbonate.

Analysis.-Calc. for C H O N S: C, 65.90; H, 4.58; N, 5.30; S, 6.00.Found: C, 66.19; H, 4.78; N, 5.60; S, 5.78.

When the foregoing procedure is repeated replacing 1-( 5'-O-trityl-8-D-ribofuranosyl -uracil with equivalent amounts of 1- (5'-O-trityl-}9-D-ribofuranosyl) -5 -chlorouracil, 1-(5'-O-trityl-3-D-ribofuranosyl -5-methylaminouracil,l-(5-O-trity1-/3-D-ribofuranosyl) -5-methyluracil,

1-( 5'-trityl-/3-D-ribofuranosyl) -5-t1ifiuoromethyluracil,l-(5-O-benzyl-fl-D-ribofuranosyl)-5-uracil, or1-(5'-O-acetyl-p-Dribofuranosyl)uracil,

there is obtained1-(5'-O-trityl-fi-D-ri'bofuranosyl)-5-chlorouracil-2',3-O-

thionocarbonate,

1-(5'-0-trity1- 8-D-ribofuranosyl)-5-methylaminouracil- 2',3'-O-thionocarbonate,

1-(5 -O-trityl-fl-D-ribofuranosyl) -5-methyluracil-2',3

O-thionocarbonate,

1-(5-O-trityl-B-D-ribofuranosyl)-5-trifiuoromethyluracil-2,3'-O-thionocarbonate,

1-(5'-O-benzyl- 3-D-ribofuranosyl)-uracil-2',3-O-

thionocarbonate, or

1-(5-O-acetyl-fl-D-ribofuranosyl) -uracil-2,3'-O- thionocarbonate,respectively.

sw m

EXAMPLE 2 1- 5 '-O-trityl-fl-D-ribofuranosyl -5-chlorouracil, -1'-5'-O-trityl-fl-D-ribofuranosyl) -5-methylaminouracil, -1-='( 5-O-trityl-/3-D'-ribofuranosyl -5-methyluracil,1-'(5'-O-trityl-;8-D-ribofuranosyl) -5-trifiuoromethyluracil, 1- 5-O-benzyl- 3-D-ribofuranosyl -uracil, or

l- 5 -O-acetyl-p-D-ribofuranosyl) -uracil are used in place of.1-(5'-O-trityl-[3-D-ribofuranosyl)- uracil.

EXAMPLE 3 1 (5 -O-trityl-B-D-ribofurzmosyl -2,3-dideoxy-2',3'- d idehdrouracil Raney nickel (1.5 g.) is boiled with 75 ml. of acetone, ml..ofethanol, and 1 ml. of ethylacetate for two hours. After addition of 1.6g. of 1-(5'-O-trity1-;8-D-ribofuranosyl)-uracil-2',3'-0-thionocarbonate,refluxing is continued for six hours. From the reaction mixture 400 mg.of 0, ,2 anhydro 1 (5 O t'rityl B D ribofuranosyl)-uracil and 250 mg. of1-(5-O-trityl-;3-D-ribofuranosyl)-2,3-dideoxy-2,3'-didehydrouracil areobtained. Fractional crystallization followed by chromatography onsilica gel achieves the separation of the two components.

Similarly, the corresponding dideoxy compounds are obtained when inplace of the uracil starting material in the above procedure there isemployed equivalent amounts of 1-(5'-O-trityl-8-D-ribofuranosyl-5-chlorouracil-2,3-O-

thionocarbonate,

1- 5 -O-trityl-B-D-ribofuranosyl) -5 -methylaminouracil-2,3'-O-thionocarbonate,

l-(5-O-trityl-;8-D-ribofuranosyl)-5-meth.yluracil-2',3'-

O-thionocarbonate,

1-(5'-O-trityl-/3-D-ribofuranosyl)-5-trifiuoromethyluracil2',3'-O-thionocarbonate,

l- 5 -O-benzyl-B-D-ribofuranosyl) -uracil-2',3 '-O- thionocarbonate, or

1-( 5 '-O-acetyl-B-D-ribofuranosyl) -uracil-2',3 '-O-thionocarbonate.

EXAMPLE 4 1-(5-O-trityl-[i-Dqibofuranosyl)-2',3-dideoxy-2',3'-dia'ehydro N -methyluracil When1-(5'-O-trityl-6-D-ribofuranosyl)-uracil-2,3'-O thionocarbonat-e isrefluxed in xylene with trimethylphosphite for 65 hours,1-(5-O-trityl-fl-D-ribofuranosyl)- 2,3-dideoxy-2',3'-didehydro-N-methyluraci1 is obtained as an amorphous product and is characterizedby NMR. Analysis.Calc. for C H N O C, 74.66; H, 5.62; N, 6.01. Found: C,74.03; H, 5.80; N, 6.16.

Similarly, the corresponding N -alkyl compounds are obtained when thetrimethylphosphite in the above procedure is replaced -by equivalentamounts of triethylphosphite, tripropylphosphite, or tributylphosphite.

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

6. What is claimed is: I 1. The process for preparing a compound of theformula:

wherein R is an acyl radical of the formula R CO- where R is lower alkylor phenyl; lower alkyl; or methyl substituted by at least one phenylgroup; R is hydrogen, halogen, lower alkyl, amino, lower alkylarnino,di(lower alkyl)amino or trifluoromethyl, which comprises treating acompound of the formula:

H l T /H OH OH wherein R is an acyl radical of the formula R CO whereinR is lower alkyl or phenyl; lower alkyl; or methyl substituted by atleast one phenyl group; R is hydrogen, halogen, lower alkyl, amino,lower alkylamino, di(lower alkyl)amino or trifluoromethyl, whichcomprises heating a compound of the formula:

R-O-CH: O N I H a H t 0 0 ll S wherein R and R are as defined above, atan elevated temperature and in the presence of a base.

5. The proces according to claim 4 wherein the base isbis-(imidazol-l-yl)-thione.

6. The process for preparing a compound of the formula:

R-O-CH: N

H H (IV) wherein R is an acyl radical of the formula R CO- where R islower alkyl or phenyl; lower alkyl; or lower alkyl substituted by atleast one phenyl group; R is hydrogen, fluoro, lower alkyl, amino, loweralkylamino, 9

di(lower alkyl)amino or trifluoromethyl, which comprises treating acompound of the formula:

\ n S (I) wherein R and R are as defined above with Raney nickel. 7. Theprocess for preparing a compound of the formula:

wherein R is an acyl radical of the formula R CO where R is lower alkylor phenyl; lower alkyl; or methyl substituted by at least one phenylgroup; R is hydrogen, fluoro, lower alkyl, amino, lower alkylamino,di(lowcr alkyl)amino or trifluoromethyl, which comprises treating acompound of the formula:

(LH OH wherein R and R are as defined above, with a thionocarbonategenerating material to form thereby a thionocarbonate compound of theformula:

9. The process for preparing a compound of the formula:

wherein R is an acyl radical of the formula R CO- where R is lower alkylor phenyl; lower alkyl; or methyl substituted by at least one phenylgroup; R is hydrogen, fluoro, lower alkyl, amino, lower alkylamino,di(lowcr alkyl)amino or trifluoromethyl; and R is lower-alkyl, whichcomprises treating a compound of the formula:

wherein R and R are as defined above, with a tri(loweralkyl)phosphite,the lower alkyl group of said tri(loweralkyl)phosphite corresponding toR.

10. The process according to claim 9 wherein the tri(lower-alkyl)phosphite is trimethylphosphite.

11. Compounds of the formula:

0 EN a H O 0 ll S wherein R is an acyl radical of the formula R CO-where R is lower alkyl or phenyl; lower alkyl; or methyl substituted byat least one phenyl group; R is hydrogen, halogen, lower alkyl, amino,lower alkylamino, di(lowcr alkyl)amino or trifiuoromethyl.

12. 1-(5-O-trityl p D-ribofuranosyl)-uracil-2,3-O- thionocarbonate.

13. Compounds of the formula:

1 O= R-O-OHz O 11% 17. Compounds of the formula:

RIM N N R-o-om 0 IO H H (V) wherein R is an acyl radical of the formulaR CO- where R is lower alkyl or phenyl; lower alkyl; or methylsubstituted by at least one phenyl group; R is hydrogen, fluoro, loweralkyl, amino, lower alkylamino, di(lower alkyl)amino or trifiuoromethyl,and R' is lower alkyl.

18. Compounds of claim 117 wherein R is trityl.

19. Compounds of claim 18 wherein R' is methyl.

20. Compound of claim 18 wherein R is hydrogen.

No references cited.

LEWIS GOTTS, Primary Examiner.

JOHNNIE R. BROWN, Assistant Examiner.

11. COMPOUNDS OF THE FORMULA:
 13. COMPOUNDS OF THE FORMULA: